► Tree rings reconstruct warm-season Upper Indus Basin (UIB) discharge since 1452. ► The UIB reconstruction is over 10 times longer than the observed discharge record. ► Novel maximum entropy bootstrap semi-parametric prediction intervals are provided. ► The reconstruction provides a context for assessing future UIB hydrologic change. ► The reconstruction can help better plan future development of UIB water resources. Water wars are a prospect in coming years as nations struggle with the effects of climate change, growing water demand, and declining resources. The Indus River supplies water to the world’s largest contiguous irrigation system generating 90% of the food production in Pakistan as well as 13gigawatts of hydroelectricity. Because any gap between water supply and demand has major and far-reaching ramifications, an understanding of natural flow variability is vital – especially when only 47years of instrumental record is available. A network of tree-ring sites from the Upper Indus Basin (UIB) was used to reconstruct river discharge levels covering the period AD 1452–2008. Novel methods tree-ring detrending based on the ‘signal free’ method and estimation of reconstruction uncertainty based on the ‘maximum entropy bootstrap’ are used. This 557-year record displays strong inter-decadal fluctuations that could not have been deduced from the short gauged record. Recent discharge levels are high but not statistically unprecedented and are likely to be associated with increased meltwater from unusually heavy prior winter snowfall. A period of prolonged below-average discharge is indicated during AD 1572–1683. This unprecedented low-flow period may have been a time of persistently below-average winter snowfall and provides a warning for future water resource planning. Our reconstruction thus helps fill the hydrological information vacuum for modeling the Hindu Kush–Karakoram–Himalayan region and is useful for planning future development of UIB water resources in an effort to close Pakistan’s “water gap”. Finally, the river discharge reconstruction provides the basis for comparing past, present, and future hydrologic changes, which will be crucial for detection and attribution of hydroclimate change in the Upper Indus Basin.